Share article

Background

In locally advanced prostate cancer, the combination of radiation therapy (RT) and androgen deprivation therapy (ADT) has been demonstrated to provide superior outcomes when compared to RT or ADT alone (Bolla, Lancet, 2002).

Indications and methodology for delivery of ADT remain uncertain and at times controversial. Outstanding questions may include duration of ADT, coordination with other treatment modalities, and type of ADT employed (androgen receptor agonist versus leutonizing hormone releasing hormone (LHRH) agonist, versus total androgen blockade using a combination of the two.

At the time when this study was designed, ADT alone was often used in locally advanced disease, especially in Europe.

Another recently published Phase III study (Widmark, Lancet, 2009) demonstrated a significant reduction in prostate-cancer-specific mortality with the addition of RT to ADT alone; however, this study used a long term androgen receptor antagonist (Flutamide) rather than an LHRH agonist

Clear results with long-term administration of a LHRH agonist with or without RT had not been reported until now.

When stratified by PSA level, there was no benefit with combined treatment observed in patients with a PSA < 20, a benefit to combined treatment in patients with a PSA between 20-50, and a more pronounced benefit to combined treatment when the PSA was > 50 ng/mL.

There was no observed difference in overall survival, and a trend towards improvement in cancer-specific survival (92% in combined arm versus 86% in ADT alone) that did not reach significance.

Authors’ Conclusions

In patients with locally advanced prostate cancer (in this study mainly T3N0M0), addition of RT to 3 years of ADT with a LHRH agonist significantly reduces the risk of clinical progression.

The follow-up is relatively limited at this point (median follow-up of 5.5 years), so the observed benefit is mainly seen in terms of loco-regional progression and not overall survival.

For distant metastases a prolonged follow up is needed to see a larger benefit.

This reduction of progression confirms that combined modality (ADT and RT) should be the standard of care for patients with a significant life expectancy diagnosed with locally advanced prostate cancer.

Clinical Implications

This trial is an important addition to a number of studies demonstrating that combined modality treatment with long-term androgen deprivation and radiation therapy is the standard of care for patients with locally advanced prostate cancer.

This study complements several other randomized Phase III data that analyze this question in slightly different ways:

The Bolla EORTC study (Lancet 2002) demonstrated that the addition of long-term hormonal therapy to RT improved overall survival in this subset of patients. The magnitude of the treatment effect in the Bolla study was greater than the magnitude in the present study, potentially supporting an argument that the incremental benefit of hormonal therapy may be greater than that of radiation therapy in these patients.

As mentioned previously, another recent study (Widmark, Lancet, 2009) demonstrated a significant reduction in prostate-cancer-specific mortality with the addition of RT to ADT alone, but in this study long-term androgen receptor blockade was used instead of an LHRH agonist.

The study presented here, somewhat unexpectedly, demonstrated that the benefit of adding RT to ADT in terms of progression-free survival appears to be correlated with baseline PSA level, with a greater benefit seen in patients with a higher baseline PSA (>50 as opposed to PSA between 20 – 50). This is intriguing but the clinical significance remains to be determined.

Potential limitations to the applicability of this study to current practice include the relatively low dose of radiation (total dose of 70 Gy) delivered, in light of the fact that dose escalation has been shown to correlate with improved outcomes.

This warrants additional investigation into the incremental benefit of combined modality therapy in the setting of RT dose escalation.

Finally, in light of recent studies demonstrating an increased risk of all-cause mortality in patients with underlying cardiovascular disease treated with ADT (Nanda, JAMA 2009), additional studies are needed to determine which patients, when stratified by cardiovascular risk factors, are likely to benefit from combined modality treatment for locally advanced prostate cancer.

Nov 4, 2011 - The addition of radiotherapy to androgen deprivation therapy is associated with improved overall survival in patients with locally advanced prostate cancer, according to a study published online Nov. 3 in The Lancet.